Mycobacterium tuberculosis, the etiological agent of TB in humans is estimated to claim two million deaths annually. Although the existing drugs possess immense value in controlling disease to some extent, they have several shortcomings. As drug discovery efforts are increasingly becoming rational, focusing at different target enzymes and identification of appropriate targets become fundamental pre-requisite.
newlineIn the present study we focused on achieving promising anti-tubercular compounds by molecular design, synthesis and anti-mycobacterial evaluation of compounds based on reported anti-tubercular agents. To explore possible targets for action we subjected the synthesized compounds for Mycobacterium tuberculosis enzyme assay against Mycobacterium tuberculosis Gyrase.
newlineIn the present work, five series of compounds (total 188 compounds) were synthesized by simple and commercially feasible methods. Out of these, 28 molecules showed gyrase IC50 less than 5 and#956;M. Among all the compounds BP_24 and IB_38 showed promising results with gyrase inhibitory potential at 0.41 and 0.72 and#956;M and good correlating supercoiling IC50 of 0.72 and 0.26 and#956;M respectively. The compounds when tested against drug sensitive strains of Mycobacterium tuberculosis exhibited MICs 48.31 and 1.38 and#956;M respectively.
newlineAmong the 188 molecules, 81 molecules were found to show supercoiling IC50 less than 5 and#956;M. With respect to supercoiling assay BZ_18 and IB_38 with IC50s of 0.51 and 0.26 and#956;M were identified as potent molecules. These compounds when tested against drug sensitive strains of Mycobacterium tuberculosis showed MICs 4.41 and 1.38 and#956;M respectively.
newlineThe safety profile of synthesized compounds was evaluated by checking their in-vitro cytotoxicity against RAW 264.7 cell line (mouse leukemic monocyte macrophage) using MTT assay.
newlineWe believe that the present class of inhibitors reported as potent, selective and no cytotoxicity with few compounds could emerge as valid leads for further chemical optimization as novel potential anti-tubercular agents.
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